Nicotine dependence (ND) is a complex behavior governed by genetic and environmental determinants. Specific polymorphisms in nAChR subunit genes have been associated with ND and other nicotine phenotypes. Varenicline is a nicotine receptor partial agonist. It treats smoking by maintaining moderate dopamine levels to reduce withdrawal (acting as an agonist) and decreasing smoking satisfaction (acting as an antagonist). Although varenicline results for smoking cessation look promising, less than half of patients are abstinent following treatment. Individual differences in response to varenicline may be related to individual differences in the effects of the drug on nicotinic acetylcholine receptor (nAChR) occupancy and its downstream influence on mesolimbic dopamine release. To date the effects of varenicline on mesolimbic dopamine release in humans have not been demonstrated nor have the moderating influences of polymorphisms within the nAChR subunit genes. Nicotine effects on mesolimbic dopamine can be studied in humans using PET imaging techniques that examine the ability of nicotine compared to placebo to induce a change in 11C-ralcopride binding potential (BP). The proposed exploratory study will randomize nicotine dependent subjects (n=30) to receive varenicline or placebo. All subjects will undergo two PET scans. First, we will image nAChRs using the alpha4beta2 subtype-specific radioligand 2-(18)F-FA-85380 in the varenicline and placebo groups. In the second scan subjects will undergo a behavioral laboratory nicotine administration procedure followed by measurement of change in raclopride BP induced by smoking a nicotinized compared to a denicotinized cigarette. Subjects will be genotyped for selected polymorphisms in the CHNRA4 and CHNRB2 gene. Throughout the study subjects will complete standardized subjective report measures of nicotine craving, withdrawal and reward. In our analyses we will examine main effects and characterize variability of varenicline and placebo effects on nAChRs occupancy, nicotine-induced change in raclopride BP and nicotine craving, withdrawal and reward. We predict a significant drug effect, with varenicline blocking the nAChRs, thereby inhibiting nicotine-induced change in raclopride BP and muting nicotine reward. We further predict variability in occupancy across subjects in both the varenicline and placebo conditions and that selected polymorphisms in the CHNA4 and CHNB2 genes will explain the variance in nAChRs occupancy, changes in nicotine-induced raclopride BP and self report measures. Findings will impact our understanding of genetic differences in these measures as well as elucidate the pharmacogenetics of treatment with varenicline. PUBLIC HEALTH RELEVANCE: The proposed research will provide significant new information of scientific and clinical relevance on individual brain and behavioral differences in response to nicotine and the medication, varenicline. This work may pave the way to the design of improved pharmacotherapies that can more effectively target the nicotinic acetylcholine and dopamine systems in the treatment of nicotine dependence.